Mechanisms and Minimization of False Discovery of Metabolic Bioorthogonal Noncanonical Amino Acid Proteomics.

Metabolic proteomics has been widely used to characterize dynamic protein networks in many areas of biomedicine, including in the arena of tissue aging and rejuvenation. Bioorthogonal noncanonical amino acid tagging (BONCAT) is based on mutant methionine-tRNA synthases (MetRS) that incorporates metabolic tags, for example, azidonorleucine [ANL], into newly synthesized proteins. BONCAT revolutionizes metabolic proteomics, because mutant MetRS transgene allows one to identify cell type-specific proteomes in mixed biological environments. This is not possible with other methods, such as stable isotope labeling with amino acids in cell culture, isobaric tags for relative and absolute quantitation and tandem mass tags. At the same time, an inherent weakness of BONCAT is that after click chemistry-based enrichment, all identified proteins are assumed to have been metabolically tagged, but there is no confirmation in mass spectrometry data that only tagged proteins are detected. As we show here, such assumption is incorrect and accurate negative controls uncover a surprisingly high degree of false positives in BONCAT proteomics. We show not only how to reveal the false discovery and thus improve the accuracy of the analyses and conclusions but also approaches for avoiding it through minimizing nonspecific detection of biotin, biotin-independent direct detection of metabolic tags, and improvement of signal to noise ratio through machine learning algorithms.

Generalization and False Memory in an Acquired Equivalence Paradigm: The Influence of Physical Resemblance Across Related Episodes.

The ability to make inferences about related experiences is an important function of memory that allows individuals to build generalizable knowledge. In some cases, however, making inferences may lead to false memories when individuals misremember inferred information as having been observed. One factor that is known to increase the prevalence of false memories is the physical resemblance between new and old information. The extent to which physical resemblance has parallel effects on generalization and memory for the source of inferred associations is not known. To investigate the parallels between memory generalization and false memories, we conducted three experiments using an acquired equivalence paradigm and manipulated physical resemblance between items that made up related experiences. The three experiments showed increased generalization for higher levels of resemblance. Recognition and source memory judgments revealed that high rates of generalization were not always accompanied by high rates of false memories. Thus, physical resemblance across episodes may promote generalization with or without a trade-off in terms of impeding memory specificity.

A game-theoretic model of Monkeypox to assess vaccination strategies.

Monkeypox (MPX) is a zoonotic disease similar to smallpox. Its fatality rate is about 11% and it is endemic to the Central and West African countries. In this paper, we analyze a compartmental model of MPX dynamics. Our goal is to see whether MPX can be controlled and eradicated by voluntary vaccinations. We show that there are three equilibria-disease free, fully endemic and previously neglected semi-endemic (with disease existing only among humans). The existence of semi-endemic equilibrium has severe implications should the MPX virus mutate to increased viral fitness in humans. We find that MPX is controllable and can be eradicated in a semi-endemic equilibrium by vaccination. However, in a fully endemic equilibrium, MPX cannot be eradicated by vaccination alone.

Assessment of ionizable, zwitterionic oximes as reactivating antidotal agents for organophosphate exposure.

Since the development in the 1950's of 2-PAM (Pralidoxime), an antidote that reactivates organophosphate conjugated acetylcholinesterase in target tissues upon pesticide or nerve agent exposure, improvements in antidotal therapy have largely involved congeneric pyridinium aldoximes. Despite seminal advances in detailing the structures of the cholinesterases as the primary target site, progress with small molecule antidotes has yet to define a superior agent. Two major limitations are immediately apparent. The first is the impacted space within the active center gorge, particularly when the active center serine at its base is conjugated with an organophosphate. The reactivating nucleophile will have to negotiate the tortuous gorge terrain to access the phosphorus atom with its most nucleophilic form or ionization state, the oximate anion. A second limitation stems from the antidote crossing the blood-brain barrier sufficiently rapidly, since it is well documented that central acetylcholinesterase inhibition gives rise to cardiovascular and respiratory compromise. The associated hypoxia then leads to a sequelae of events, including poor perfusion of the brain and periphery, along with muscle fasciculation, tremors and eventually seizures. We consider both the barriers confronting and further achievements necessary to enhance efficacy of antidotes.

Synthesis of Cu-In-S ternary nanocrystals with tunable structure and composition.

Nearly monodisperse Cu-In-S ternary nanocrystals with tunable composition, crystalline structure, and size were synthesized by a hot-injection method using mixed generic precursors. Such ternary nanocrystals with zincblende and wurtzite structure were reported for the first time. This work correlates the crystalline structure of the binary ZnS nanoparticles with those of ternary Cu-In-S nanocrystals, demonstrating the feasibility of making their alloyed or core/shell structure. Furthermore, this work may provide suitable material candidates for low-cost, high-efficiency solar cell fabrication.

Maternal depressive symptoms at 2 to 4 months post partum and early parenting practices.

OBJECTIVE: To determine whether maternal depressive symptoms, reported when infants are 2 to 4 months old, are associated with mothers' early parenting practices. DESIGN: Secondary data analyses collected from the National Evaluation of Healthy Steps for Young Children. Data sources included newborn enrollment questionnaires and parent interviews when infants were 2 to 4 months old. Maternal depressive symptoms were assessed using the Center for Epidemiological Studies Depression Scale. SETTING: Twenty-four pediatric practices across the United States. PARTICIPANTS: A total of 5565 families enrolled in Healthy Steps; 4874 mothers (88%) completed 2- to 4-month interviews and provided Center for Epidemiologic Studies Depression Scale data; 17.8% of mothers reported having depressive symptoms. MAIN OUTCOME MEASURES: Ten parenting practices assessed in 3 domains: safety (sleep position and lowering water temperature), feeding (cereal, water, or juice; continuing breastfeeding), and practices to promote child development (showing books, playing with infant, talking to infant, and following 2 or more routines). RESULTS: Mothers with and without depressive symptoms reported similar uses of safety and feeding practices. Mothers with depressive symptoms had reduced odds of continuing breastfeeding (adjusted odds ratio [AOR], 0.73; 95% confidence interval [CI], 0.61-0.88), showing books (AOR, 0.81; 95% CI, 0.68-0.97), playing with the infant (AOR, 0.70; 95% CI, 0.54-0.90), talking to the infant (AOR, 0.74; 95% CI, 0.63-0.86), and following routines (AOR, 0.61; 95% CI, 0.52-0.72). CONCLUSION: Maternal depressive symptoms are common in early infancy and contribute to unfavorable parenting practices.

Developmental specialists in pediatric practices: perspectives of clinicians and staff.

OBJECTIVE: To investigate how introducing early child-development specialists (Healthy Steps Specialists) and enhanced developmental services into routine pediatric care affects perspectives of clinicians and staff. METHODS: Self-administered questionnaires were completed at baseline and at 30 months by clinicians, clinical staff, and nonclinical staff at pediatric sites participating in the evaluation of the Healthy Steps for Young Children Program. The evaluation included 6 randomization and 9 quasi-experimental sites. Barriers to providing well-child care, visit length, perceptions of care provided, and topics discussed with parents were assessed. RESULTS: Over time, despite persistent barriers to delivering high-quality services, clinicians were more likely to report being satisfied with their clinical staff's ability to meet developmental and behavioral needs of children. Moreover, clinicians were more likely to report discussing the importance of routines with control rather than with intervention families, suggesting a reliance on Healthy Steps Specialists. There was no effect on visit length. Thirty months after introducing Healthy Steps Specialists and enhanced services, nearly all clinicians agreed or strongly agreed that the Healthy Steps Specialists talked with parents about their child's development, showed them activities to do with their child, and provided emotional support. Involvement of the Healthy Steps Specialist in these activities was reported more by clinicians than by clinical staff and least by nonclinical staff. CONCLUSIONS: Clinicians acknowledged the activities performed by and contributions of the developmental specialists. Differences in perspectives of personnel may reflect different interactions among families, developmental specialists, and practice staff.

A practice-based intervention to enhance quality of care in the first 3 years of life: the Healthy Steps for Young Children Program.

CONTEXT: There is growing concern regarding the quality of health care available in the United States for young children, and specific limitations have been noted in developmental and behavioral services provided for children in the first 3 years of life. OBJECTIVE: To determine the impact of the Healthy Steps for Young Children Program on quality of early childhood health care and parenting practices. DESIGN, SETTING, AND PARTICIPANTS: Prospective controlled clinical trial enrolling participants between September 1996 and November 1998 at 6 randomization and 9 quasi-experimental sites across the United States. Participants were 5565 children enrolled at birth and followed up through age 3 years. INTERVENTION: Incorporation of developmental specialists and enhanced developmental services into pediatric care in participants' first 3 years of life. MAIN OUTCOME MEASURES: Quality of care was operationalized across 4 domains: effectiveness (eg, families received > or =4 Healthy Steps-related services or discussed >6 anticipatory guidance topics), patient-centeredness (eg, families were satisfied with care provided), timeliness (eg, children received timely well-child visits and vaccinations), and efficiency (eg, families remained at the practice for > or =20 months). Parenting outcomes included response to child misbehavior (eg, use of severe discipline) and practices to promote child development and safety (eg, mothers at risk for depression discussed their sadness with someone at the practice). RESULTS: Of the 5565 enrolled families, 3737 (67.2%) responded to an interview at 30 to 33 months (usual care, 1716 families; Healthy Steps, 2021 families). Families who participated in the Healthy Steps Program had greater odds of receiving 4 or more Healthy Steps-related services (for randomization and quasi-experimental sites, respectively: odds ratio [OR], 16.90 [95% confidence interval [CI], 12.78 to 22.34] and OR, 23.05 [95% CI, 17.38 to 30.58]), of discussing more than 6 anticipatory guidance topics (OR, 8.56 [95% CI, 6.47 to 11.32] and OR, 12.31 [95% CI, 9.35 to 16.19]), of being highly satisfied with care provided (eg, someone in the practice went out of the way for them) (OR, 2.06 [95% CI, 1.64 to 2.58] and OR, 2.11 [95% CI, 1.72 to 2.59]), of receiving timely well-child visits and vaccinations (eg, age-appropriate 1-month visit) (OR, 1.98 [95% CI, 1.08 to 3.62] and OR, 2.11 [95% CI, 1.16 to 3.85]), and of remaining at the practice for 20 months or longer (OR, 2.02 [95% CI, 1.61 to 2.55] and OR, 1.75 [95% CI, 1.43 to 2.15]). They also had reduced odds of using severe discipline (eg, slapping in face or spanking with object) (OR, 0.82 [95% CI, 0.54 to 1.26] and OR, 0.67 [95% CI, 0.46 to 0.97]). Among mothers considered at risk for depression, those who participated in the Healthy Steps Program had greater odds of discussing their sadness with someone at the practice (OR, 0.95 [95% CI, 0.56 to 1.63] and OR, 2.82 [95% CI, 1.57 to 5.08]). CONCLUSION: Universal, practice-based interventions can enhance quality of care for families of young children and can improve selected parenting practices.

Novel solution processing of high-efficiency Earth-abundant Cu2 ZnSn(S,Se)4 solar cells.

A novel solution-based approach is presented to process earth-abundant Cu(2)ZnSn(S,Se)(4) absorbers using fully dissolved CZTS precursors in which each of the elemental constituents intermix on a molecular scale. This method enables the low-temperature processing of chemically clean kesterite films with excellent homogeneity. The high performance of resulting optoelectronic devices represents a chance to extend the impact of CZTS into the next chapter of thin-film solar cells.

Influence of zeolite crystal size on zeolite-polyamide thin film nanocomposite membranes.

Zeolite-polyamide thin film nanocomposite membranes were coated onto polysulfone ultrafiltration membranes by interfacial polymerization of amine and acid chloride monomers in the presence of Linde type A zeolite nanocrystals. A matrix of three different interfacial polymerization chemistries and three different-sized zeolite crystals produced nanocomposite thin films with widely varying structure, morphology, charge, hydrophilicity, and separation performance (evaluated as reverse osmosis membranes). Pure polyamide film properties were tuned by changing polymerization chemistry, but addition of zeolite nanoparticles produced even greater changes in separation performance, surface chemistry, and film morphology. For fixed polymer chemistry, addition of zeolite nanoparticles formed more permeable, negatively charged, and thicker polyamide films. Smaller zeolites produced greater permeability enhancements, but larger zeolites produced more favorable surface properties; hence, nanoparticle size may be considered an additional "degree of freedom" in designing thin film nanocomposite reverse osmosis membranes. The data presented offer additional support for the hypothesis that zeolite crystals alter polyamide thin film structure when they are present during the interfacial polymerization reaction.

Healthy Steps for Young Children: sustained results at 5.5 years.

OBJECTIVE: We sought to determine whether Healthy Steps for Young Children has sustained treatment effects at 5.5 years, given early findings demonstrating enhanced quality of care and improvements in selected parenting practices. METHODS: Healthy Steps was a clinical trial that incorporated developmental specialists and enhanced developmental services into pediatric care in the first 3 years of life. A total of 5565 children were enrolled at birth and followed through 5.5 years. Healthy Steps was evaluated at 6 randomization and 9 quasi-experimental sites. Computer-assisted telephone interviews were conducted with mothers when Healthy Steps children were 5.5 years of age. Outcomes included experiences seeking care, parent response to child misbehavior, perception of child's behavior, and parenting practices to promote development and safety. Logistic regression was used to estimate overall effects of Healthy Steps, adjusting for site and baseline demographic characteristics. RESULTS: A total of 3165 (56.9%) families responded to interviews (usual care: n = 1441; Healthy Steps: n = 1724). Families that had received Healthy Steps services were more satisfied with care (agreed that pediatrician/nurse practitioner provided support, 82.0% vs 79.0%; odds ratio: 1.25 [95% confidence interval: 1.02-1.53]) and more likely to receive needed anticipatory guidance (54.9% vs 49.2%; odds ratio: 1.33 [95% confidence interval: 1.13-1.57]) (all P < .05). They also had increased odds of remaining at the original practice (65.1% vs 61.4%; odds ratio: 1.19 [95% confidence interval: 1.01-1.39]). Healthy Steps families reported reduced odds of using severe discipline (slap in face/spank with object, 10.1% vs 14.1%; odds ratio: 0.68 [95% confidence interval: 0.54-0.86]) and increased odds of often/almost always negotiating with their child (59.8% vs 56.3%; odds ratio: 1.20 [95% confidence interval: 1.03-1.39]). They had greater odds of reporting a clinical or borderline concern regarding their child's behavior (18.1% vs 14.8%; odds ratio: 1.35 [95% confidence interval: 1.10-1.64]) and their child reading books (59.4% vs 53.6%; odds ratio: 1.16 [95% confidence interval: 1.00-1.35]). There were no effects on safety practices. CONCLUSIONS: Sustained treatment effects, albeit modest, are consistent with early findings. Universal, practice-based interventions can enhance quality of care for families with young children and can improve selected parenting practices beyond the duration of the intervention.

The timing of maternal depressive symptoms and mothers' parenting practices with young children: implications for pediatric practice.

BACKGROUND: The prevalence of maternal depressive symptoms and its associated consequences on parental behaviors, child health, and development are well documented. Researchers have called for additional work to investigate the effects of the timing of maternal depressive symptoms at various stages in the development of the young child on the emergence of developmentally appropriate parenting practices. For clinicians, data are limited about when or how often to screen for maternal depressive symptoms or how to target anticipatory guidance to address parental needs. PURPOSE: We sought to determine whether concurrent maternal depressive symptoms have a greater effect than earlier depressive symptoms on the emergence of maternal parenting practices at 30 to 33 months in 3 important domains of child safety, development, and discipline. METHODOLOGY: Secondary analyses from the Healthy Steps National Evaluation were conducted for this study. Data sources included a self-administered enrollment questionnaire and computer-assisted telephone interviews with the mother when the Healthy Steps children were 2 to 4 and 30 to 33 months of age. The 30- to 33-month interview provided information about 4 safety practices (ie, always uses car seat, has electric outlet covers, has safety latches on cabinets, and lowered temperature on the water heater), 6 child development practices (ie, talks daily to child while working, plays daily with child, reads daily to child, limits child television and video watching to <2 hours a day, follows > or = 3 daily routines, and being more nurturing), and 3 discipline practices (ie, uses more reasoning, uses more harsh punishment, and ever slapped child on the face or spanked the child with an object). The parenting practices were selected based on evidence of their importance for child health and development, near complete data, and sample variability. The discipline practices were constructed from the Parental Response to Misbehavior Scale. Maternal depressive symptoms were assessed using a 14-item modified version of the Center for Epidemiologic Studies-Depression Scale. Multiple logistic regression models estimated the effect of depressive symptoms on parenting practices, adjusted for baseline demographic characteristics, Healthy Steps participation, and site. No significant interactions were found when testing analytic models with dummy variables for depressive symptoms at 2 to 4 months only, 30 to 33 months only, and at both times; reported models do not include interaction terms. We report main effects of depressive symptoms at 2 to 4 and 30 to 33 months when both are included in the model. RESULTS: Of 5565 families, 3412 mothers (61%) completed 2- to 4- and 30- to 33-month interviews and provided Center for Epidemiologic Studies-Depression Scale data at both times. Mothers with depressive symptoms at 2 to 4 months had reduced odds of using car seats, lowering the water heater temperature, and playing with the child at 30 to 33 months. Mothers with concurrent depressive symptoms had reduced odds of using electric outlet covers, using safety latches, talking with the child, limiting television or video watching, following daily routines, and being more nurturing. Mothers with concurrent depressive symptoms had increased odds of using harsh punishment and of slapping the child on the face or spanking with an object. CONCLUSIONS: The study findings suggest that concurrent maternal depressive symptoms have stronger relations than earlier depressive symptoms, with mothers not initiating recommended age-appropriate safety and child development practices and also using harsh discipline practices for toddlers. Our findings, however, also suggest that for parenting practices that are likely to be established early in the life of the child, it may be reasonable that mothers with early depressive symptoms may continue to affect use of those practices by mothers. The results of our study underscore the importance of clinicians screening for maternal depressive symptoms during the toddler period, as well as the early postpartum period, because these symptoms can appear later independent of earlier screening results. Providing periodic depressive symptom screening of the mothers of young patients has the potential to improve clinician capacity to provide timely and tailored anticipatory guidance about important parenting practices, as well as to make appropriate referrals.

Maternal depressive symptoms and children's receipt of health care in the first 3 years of life.

BACKGROUND: Maternal depression is widely recognized to negatively influence mother-child interactions and children's behavior and development, but little is known about its relation to children's receipt of health care. OBJECTIVE: To determine if maternal depressive symptoms reported at 2 to 4 and 30 to 33 months postpartum are associated with children's receipt of acute and preventive health care services in the first 30 months. DESIGN: Cohort study of data collected prospectively as part of the National Evaluation of Healthy Steps for Young Children (HS). Data sources included medical records abstracted for the first 32 months, enrollment questionnaires, and parent interviews when children were 2 to 4 and 30 to 33 months old. Acute care use included hospitalizations and emergency department visits. Preventive care included well-child visits and vaccinations. Maternal depressive symptoms were assessed by using the Center for Epidemiologic Studies-Depression Scale. Generalized linear models (logistic regression for dichotomous outcomes and Poisson regression for count outcomes) were used to estimate the effect of maternal depressive symptoms on children's receipt of care. The models were adjusted for baseline demographic characteristics, child health status, participation in HS, and site of enrollment. RESULTS: Of the 5565 families enrolled in HS, 88% completed 2- to 4-month parent interviews, 67% completed 30- to 33-month parent interviews, and 96% had medical records abstracted. The percentages of mothers reporting depressive symptoms were 17.8% at 2 to 4 months, 15.5% at 30 to 33 months, and 6.4% at both. Children whose mothers had depressive symptoms at 2 to 4 months had increased use of acute care reported at 30 to 33 months including emergency department visits in the past year (odds ratio [OR]: 1.44; confidence interval [CI]: 1.17, 1.76). These children also had decreased receipt of preventive services including age-appropriate well-child visits (eg, at 12 months [OR: 0.80; CI: 0.67, 0.95]) and up-to-date vaccinations at 24 months for 4 doses of diphtheria, tetanus, pertussis, 3 doses of polio vaccine, and 1 dose of measles-mumps-rubella (OR: 0.79; CI: 0.68, 0.93). There was no association of maternal depressive symptoms at 30 to 33 months with children's preceding use of care. CONCLUSIONS: Maternal depressive symptoms in early infancy contribute to unfavorable patterns of health care seeking for children. Increased provider training for recognizing maternal depressive symptoms in office settings, more effective systems of referral, and development of partnerships between adult and pediatric providers could contribute to enhanced receipt of care among young children.

Narrowing the income gaps in preventive care for young children: families in healthy steps.

Persistent unmet preventive and developmental health care needs of children in low-income families are a national concern. Recently, there have been efforts to promote developmental services as part of primary care for all young children. However, there is limited research to determine whether the neediest families are well in universal interventions. In our study, we assessed if disparities persist in utilization of developmental services, well child care, and satisfaction with care among low-, middle-, and high-income families participating in Healthy Steps for Young Children. Healthy Steps is a national experiment that incorporated developmental services into primary care for children from birth to 3 years of age. In the United States, 15 pediatric practices participated in this prospective study. At birth, 2,963 children were enrolled between September 1996 and November 1998 and followed through 33 months of age. The utilization of developmental services, satisfaction with care, and receipt of age-appropriate well child visits were measured at 30-33 months and adjusted for demographic and economic covariates. We found that the adjusted odds of low-income families did not differ from high-income families in receipt of four or more Healthy Steps services, a home visit, or discussing five or more child rearing topics. Low- and middle-income families had reduced adjusted odds of receiving a developmental assessment and books to read. The adjusted odds of low- and middle-income families did not differ from high-income families in being very satisfied with care provided or receiving age-appropriate well child visits. A universal practice-based intervention such as Healthy Steps has the potential to reduce income disparities in the utilization of preventive services, timely well child care, and satisfaction with care.